Project Summary/Abstract Acute mental status changes, classified as encephalopathy or delirium, affect a large proportion of hospital patients and increase morbidity, especially in elderly and/or patients with neurodegenerative diseases. In turn, increasing evidence shows that these acute insults potentially fuel long term neurodegeneration. Apart from increased morbidity, these mental status changes also increase length and cost of hospital stays by resulting in accidents and unnecessary neurological consults, propagating unnecessary delegations of hospital resources. Despite this major pathologic and monetary burden, little is understood about the underlying mechanisms leading to acute encephalopathy. This is largely due to the absence of a fully defined animal model and further, a quick and reliable read out of encephalopathic progression/delirium in an animal model. Many cases of delirium are triggered by systemic infection, even when the CNS is not directly involved, which leads to a cascade of inflammatory pathways from or across the blood brain barrier. Studies have shown systemic infectious insults resulting in an upregulation of common inflammatory mediators within brain tissue that likely contribute to glial activation and resultant synapse dysregulation. Here, we use lipopolysaccharide (LPS), a cell wall component on gram negative bacteria known to cause systemic as well as neuroinflammation, as a systemic agent to model acute septic encephalopathy (ASE) in mice. We follow the impact of this inflammatory insult in healthy, adult mice. Further, we propose neuroimaging, specifically, recently developed calcium neural functional connectivity (FC) monitoring, to establish an FC readout of delirium in this model of ASE. Preliminary data has shown acute degradation of neural functional networks 24Hrs post LPS injection. This project will use this biomarker as a means to develop a read out of ASE/delirium in an animal model and probe regional upregulation of inflammatory mediators and synapse integrity during periods of altered FC. I hypothesize that this acute degradation of FC will parallel behavioral deficits and reflect regional upregulation of inflammatory mediators resulting in synapse elimination. A battery of behavioral data will be collected and used to help interpret the model as a whole. Further, development of this animal model will allow for cellular and molecular studies of this disease to progress, specifically with my additional hypothesis that acute synapse elimination and microglial priming is complement-mediated. Many studies have pointed to complement, especially protein C3a, as an important regulator post LPS administration, and complement in general has been show to drive synaptic pruning during development and elimination in a variety of neuroinflammatory diseases. It will thus be important to understand the role of complement in acute encephalopathy. This work as a whole sets up a means to study the underlying mechanisms involved in delirium/ASE and future work will begin investigating long term impacts on neurodegeneration.